Incident users of tyrosine kinase inhibitors in patients with chronic myeloid leukemia: Analysis of anticancer treatment trajectories—A French population‐based study using the French national health data system
Authors: Clémentine Vabre, Yoann Zelmat, Martin Gauthier, Marie Pajiep, Cécile Conte, Maryse Lapeyre‐Mestre, Rosemary Dray‐Spira, Mahmoud Zureik, Fabien Despas
Journal: American Journal of Hematology (2022)

To the Editor: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm mainly characterized by the excessive production of white blood cells. In 2018, the CML incidence in France was approximately 1.0–1.5/100 000 persons with a median age of 60–62 years, 55% of whom were men.1 The first tyrosine kinase inhibitor (TKI) was imatinib, approved in 2001, which have improved the prognosis of this disease with patients reaching the life expectancy of the general population. Due to resistance or adverse drug reactions, other drugs have been developed for this indication: dasatinib and nilotinib, both recommended for first-line treatment (LT) by the European LeukemiaNet (ELN), bosutinib, and ponatinib.2 Few data are available regarding the real-life use of TKIs for CML, especially on the entire population of a country, but these data can provide a description of care pathways, which are sometimes complex in real-life conditions.3-5 The objective of this study was to describe TKI treatment courses in patients with CML who initiated treatment between 2014 and 2017 and who were followed for 3 years, using data from the French Health Data System (SNDS). This study was based on the SNDS, which covers 99% of the French population (i.e., approximately 67 million inhabitants) and compiles several data from two sources: the French health insurance claims database and the French hospital and discharge database (online supplementary method). We included all adult patients (≥18 years old) newly treated with TKI for CML: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, between 01 January 2014 and 31 December 2017 in France. Patients with CML were identified using an algorithm already used within the SNDS6 (Table S1). Incident TKI users were defined as having at least one reimbursement for a TKI of interest between 01 January 2014 and 31 December 2017 and no TKI reimbursement during the 2 years prior to the first reimbursement. The index date is the date of the first reimbursement of TKI. Each patient was followed 3 years after the index date, that is, until 2020 for patients included in 2017, or until disease progression, defined as the blast phase (BP), or death, whichever came first. The five TKIs were identified in the database using the ATC code (Table S1). The first TKI was defined as the TKI dispensed at the index date. If the patient received ≥2 different TKIs, the 2-LT was defined as the second TKI prescribed chronologically and so on for the subsequent LT (third, fourth, fifth). Individuals who switched were defined as patients with at least two different TKIs during follow-up. The time frame was defined as the period between the index date and the date of the switch. A treatment interruption was defined as a gap of 90 days or more between two TKI dispensations. Medical comorbidities were identified at the index date, for the five previous years, using LTD and hospital diagnostic codes according to ICD-10 (Table S1). A Sankey diagram was designed to visualize the different LT for each patient using SankeyMatic. Characteristics of TKI utilization and time frames were described in relation to the first-line TKI. Cumulative incidence functions of the first switch according to the first TKI prescription and Gray's test (competitive risk, in our case death and BP, were taken into account) were used to estimate whether occurrence of the first switch was different. To determine whether the utilization pattern differed over time, we also described first-line and second-line prescription according to the year of prescription. Analyses were carried out using the SAS EG® 7.15 software. Of the 8701 individuals with a first TKI reimbursement between 2014 and 2017, we identified 4162 CML adults newly treated with a TKI (Figure S1). The median age was 62 years and 56.3% of the patients were male (Table S1). More than 16.5% had cardiovascular comorbidities, 15.7% diabetes and 42.2% had antihypertensive drugs.1-L imatinib patients were older than 1-L nilotinib or dasatinib patients (median age, years): 65 versus 49 and 52 respectively, and had more comorbidities (cardiovascular comorbidities: 19.5% vs. 4.4% and 10.2%). During the 3-year follow-up, death occurred in 10.8% and progression to BP in 1.6% (median time of 526 and 454 days, respectively) of the patients. CML patients with death or disease progression presented more comorbidities (Table S1). Approximately 70% of the overall population had only one TKI during the 3-year follow-up and among individuals alive and in the chronic phase at the end of follow-up, 88% were still under TKI treatment (Table S1). Individuals had approximately one dispensation per month with a median of 34 dispensations [IQR: 24–37] over the 36 months with a median time of 30 days [27–35] between dispensations. Treatment was interrupted for approximately 20% of the patients. The main 1-LT were imatinib (78.4%) and nilotinib (18.2%). Dasatinib was the main 2-LT prescribed (approximately 70%) and nilotinib the main 3-LT (33%). Bosutinib and ponatinib were mainly prescribed in 2-LT or a subsequent line, unlike imatinib (Figure 1). More frequent courses were patients on imatinib alone (53%) followed by imatinib-dasatinib or nilotinib alone (both 12%). Approximately 32% of the individuals switched at least once. Half of the population that switched did so the first time during the first year of treatment (median time [IQR]: 356 days [174–549]). During the first and second year of follow-up, a switch occurred in 17.0% and 14.4% in 1-LT imatinib patients, 13.2% and 15.3% in 1-LT nilotinib patients and 16.4% and 15.7%, respectively, in 1-LT dasatinib patients. TKI switch during follow-up was not significantly different in patients who started with imatinib, nilotinib, and dasatinib (Gray's test; p = .86, Figure S1). The pattern of first-line prescription was similar across the study period (imatinib: 75%–80%, nilotinib: 16%–20%) (Figure S1). Second-line prescription differed over time, with bosutinib and ponatinib becoming more and more prescribed while dasatinib and nilotinib prescriptions decreased. In this study, TKI LT initiation in new patients with CML is consistent with a previous SNDS study (2011–2014) and with ELN recommendations (2013).2, 5 Imatinib and nilotinib accounted for 95% of the initial treatments, while dasatinib was not legally reimbursed in 1-LT in France but was mainly used in 2-LT. While the rate of initial imatinib prescription is the same across studies (approximately 80% of the patients), the TKI used in 2-LT differs according to the country: either nilotinib was the main TKI used in 2-LT, or nilotinib and dasatinib were used at equal rates for 2-LT.3, 5 Characteristics of the CML population described in our study are similar to the CML population in a French cancer registry in terms of age and gender ratio (median age of 62 years and 56% male) and is consistent with the incidence rate in France.1 1-LT imatinib patients were older and had more comorbidities than 1-LT nilotinib patients, which is consistent with other studies and recommendations since imatinib is a safer option for patients with comorbidities, although it may be less potent. Initial TKI prescription took contraindications into account and potential TKI side effects. Dasatinib was less likely to be initiated in patients with respiratory comorbidities and those who started with nilotinib had fewer comorbidities, especially cardiovascular comorbidities, peripheral arterial diseases and stroke. The results of this study also showed chronic use of TKI treatments in CML patients (median of 34 dispensations during the 36-month follow-up). Switches rate in the first and second year were similar to that found in the SIMPLICITY study.4The SNDS covers the entire French population, which allowed us to exhaustively describe TKI LT at a national level. We used an identification algorithm previously used and similar to another which has been validated to identify patients with CML in this database.5, 6 Exposure to drugs was identified through reimbursement data prospectively collected, thereby avoiding recall and misclassification biases. We had no information on drug administration, but chronic use of this treatment with a dispensation every month substantially limits this type of bias. Dispensation drugs within clinical trials are not identifiable in the SNDS, and some dispensations may not have been taken into account for the identification of LT or treatment characteristics. However, the number of dispensations in this setting is expected to be low as most clinical trials that included CML patients in France had already ended before the study period or were to end at the end of December 2014. We do not have access to clinical data such as the EUTOS score or results of biological tests, neither can we identify reasons for TKI switches. However, we had information for patients' comorbidities with diagnostic codes (CIM-10) in hospitalized patients and dispensation of all reimbursed drugs in an outpatient setting (antidiabetics, anti-hypertensive drugs…). We also did not have clinical information about disease progression, treatment intolerance or level of response. We identified CML patients who were hospitalized for BP and this rate might be underestimated. This study illustrates the plurality of TKI treatment courses in real life, in newly diagnosed CML patients over a recent period and at a national level, and provides information about real-life practice. Study design: Clémentine Vabre, Mahmoud Zureik, Fabien Despas. Data acquisition and statistical analysis: Clémentine Vabre, Yoann Zelmat, Marie Pajiep, Cécile Conte. Analysis and interpretation: Clémentine Vabre, Martin Gauthier, Maryse Lapeyre-Mestre, Rosemary Dray-Spira, Mahmoud Zureik, Fabien Despas. Drafting of the manuscript: Clémentine Vabre, Mahmoud Zureik, Fabien Despas. Critical review of the manuscript for significant intellectual content: Clémentine Vabre, Yoann Zelmat, Martin Gauthier, Marie Pajiep, Cécile Conte, Maryse Lapeyre-Mestre, Rosemary Dray-Spira, Mahmoud Zureik, Fabien Despas. Clémentine Vabre and Mahmoud Zureik had full access to study data and are responsible for data integrity and accurate analysis. We acknowledge TTP Amplus for the English revision of the manuscript, Jérome Droin and Bérangère Baricault for their assistance in using the SNDS. The authors have no conflict of interest to declare. According to data protection and the French regulation, the authors cannot publicly share the data from the SNDS. However, any person or structure, public or private, for-profit or non-profit, is able to access SNDS data upon authorization from the CNIL, in order to carry out a study, a research or an evaluation of public interest (https://www.snds.gouv.fr). Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.